Non-crystalline oxidized glutathione and production method therefor

ABSTRACT

A non-crystalline amorphism of oxidized glutathione is produced by drying a crystal of oxidized glutathione hexahydrate at a temperature of 40 to 90° C.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the U.S. national phase of InternationalPatent Application PCT/JP2011/059777, filed on Apr. 21, 2010, whichclaims the benefit of Japanese Patent Application No. 2010-097530, filedon Apr. 21, 2010, which are incorporated by reference in theirentireties herein.

TECHNICAL FIELD

The present invention relates to a crystal of oxidized glutathioneuseful as a product, raw material, intermediate or the like ofhealth-aid food, pharmaceuticals, cosmetics or the like, and a processfor producing the crystal.

BACKGROUND ART

Oxidized glutathione has the same actions as reduced glutathione, and asactions of oxidized glutathione, for example, hepatic detoxificationaction via oral administration, and the like are known (Non-PatentDocument 1). Due to this, oxidized glutathione may be used for variousapplications in which reduced glutathione has been used, and is useful,for example, as a product, raw material or intermediate of health-aidfood, pharmaceuticals, cosmetics, and the like.

Known process for producing oxidized glutathione include a process inwhich an aqueous solution or yeast extract solution containing oxidizedglutathione obtained by a fermentation process, enzymatic process or thelike is used as a starting material, and in the aqueous solution oryeast extract solution, the reduced glutathione is converted into theoxidized glutathione to obtain a solution of oxidized glutathione, andthen by conducting a concentration, a dilution and the like, an aqueoussolution or yeast extract solution containing the oxidized glutathioneis obtained (Patent Documents 1 and 2); a method for obtaining powder ofyeast extract solution containing oxidized glutathione by addingexcipients and the like, and freeze-drying, spray-drying or the like(Patent Document 2); a process for producing a crystal of oxidizedglutathione monohydrate by adding alcohol and the like dropwise to anaqueous solution containing oxidized glutathione (Patent Document 3); aprocess for producing a crystal of oxidized glutathione octahydrate(Non-Patent document 2) and the like.

However, it is known that the production method by freeze-drying asolution of oxidized glutathione shows poor impurity selectivity andrequire a large amount of energy for freeze-drying so that it is notsuitable for industrialization. Meanwhile, the method based onspray-drying is known to show an increase in impurities due to thermalcontact.

In addition, it is known that the crystal of oxidized glutathioneoctahydrate is problematic in that the content of water contained in thecrystal is not uniform, and shows poor stability and a long time up to3-4 days is required to obtain the crystal, and that the crystal ofoxidized glutathione monohydrate leave room for improvement in thatcrystal separation capability is poor because it is a needle-likecrystal and easily agglomerate, impurity selectivity (purificationability) is poor and crystal growth rate is slow.

Therefore, there is a need for a crystal of oxidized glutathione thathas excellent stability and is handled industrially with ease.

PRIOR ART Patent Document

[Patent Document 1] Japanese Patent Application Laid-Open No. Hei5-146279

[Patent Document 2] Japanese Patent Application Laid-Open No. Hei7-177896

[Patent Document 3] Japanese Patent No. 4401775

Non-Patent Document

[Non-Patent Document 1] J. Nutr. Sci., 44, pp 613 (1998)

[Non-Patent Document 2] 1999 International Union of Crystallograpy, pp1538 (1999)

DISCLOSURE OF INVENTION Problems to Be Solved by the Invention

An object of the present invention is to provide a non-crystallineamorphism of oxidized glutathione useful as a product, raw material,intermediate or the like of health-aid food, pharmaceuticals, cosmeticsand the like, and a process for producing thereof.

Means for Solving the Problems

The present invention relates to the following (1) to (8).

(1) A process for producing a non-crystalline amorphism of oxidizedglutathione characterized by drying a crystal of oxidized glutathionehexahydrate at a temperature of 40 to 90° C.

(2) The process for producing a non-crystalline amorphism of oxidizedglutathione according to (1), wherein the crystal of oxidizedglutathione hexahydrate is a crystal of oxidized glutathione hexahydratehaving peaks at a diffraction angle (2θ) of 8.12°, 9.70°, 10.62°,12.44°, 14.20°, 16.22°, 16.38°, 17.90°, 18.90°, 19.52°, 20.26°, 21.32°,21.60°, 22.82°, 23.34°, 24.40°, 24.72°, 24.98°, 25.56°, 26.18°, 26.68°,27.20°, 28.32°, 29.00°, 29.66°, 31.02°, 31.58°, 32.20°, 32.72°, 32.88°,34.48° and 41.56° in powder X-ray diffraction.

(3) The process for producing a non-crystalline amorphism of oxidizedglutathione according to (1) or (2), characterized in that the crystalof oxidized glutathione hexahydrate is obtained by cooling an aqueoussolution containing oxidized glutathione to 15° C. or lower toprecipitate a crystal of oxidized glutathione hexahydrate, and thencollecting the crystals of oxidized glutathione hexahydrate from theaqueous solution.

(4) The process for producing a non-crystalline amorphism of oxidizedglutathione according to (1) or (2), characterized in that the crystalof oxidized glutathione hexahydrate is obtained by a method comprising astep of adding or adding dropwise a solvent selected from the groupconsisting of alcohols and ketones to an aqueous solution containingoxidized glutathione at 15° C. or lower.

(5) The process for producing a non-crystalline amorphism of oxidizedglutathione according to (1) or (2), characterized in that the crystalof oxidized glutathione hexahydrate is obtained by a method comprising astep of adding or adding dropwise a solvent selected from the groupconsisting of methanol, ethanol, n-propanol and isopropyl alcohol to anaqueous solution containing oxidized glutathione at 15° C. or lower.

(6) The process for producing a non-crystalline amorphism of oxidizedglutathione according to (1) or (2), characterized in that the crystalof oxidized glutathione hexahydrate is obtained by a method comprising astep of adding or adding dropwise methanol to an aqueous solutioncontaining oxidized glutathione at 15° C. or lower.

(7) The process for producing a non-crystalline amorphism of oxidizedglutathione according to any one of (3) to (6), wherein the aqueoussolution containing oxidized glutathione is an aqueous solution obtainedby treating a solution containing oxidized glutathione with a syntheticadsorbent resin or ion exchange resin.

(8) A non-crystalline amorphism of oxidized glutathione obtained by theprocess according to any one of (1) to (7).

Effects of the Invention

According to the present invention, there are provided a non-crystallineamorphism of oxidized glutathione useful as a product, raw material,intermediate or the like of health-aid food, pharmaceuticals, cosmeticsand the like, and a process for producing thereof.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

In the present invention, the solution of oxidized glutathione may beany solution containing oxidized glutathione, but examples thereof mayinclude an aqueous solution, culture solution, yeast extract, solutionbacteriostatic solution and the like containing oxidized glutathioneobtained by acquiring reduced glutathione prepared via a syntheticmethod, fermentation method or method of extraction from yeast, forexample, according to a method described in Japanese Patent PublicationNo. Sho 44-239, Japanese Patent Publication No. Sho 46-4755, JapanesePatent Publication No. Sho 46-2838 or Japanese Patent ApplicationLaid-Open No. Sho 61-74595, as a reaction solution containing reducedglutathione as it is, or, for example, as a purified solution,freeze-dried powder or the like, and oxidizing the acquired reducedglutathione with, for example, oxygen, hydrogen peroxide, enzyme capableof oxidizing ascorbic acid or the like according to a method describedin Japanese Patent Application Laid-Open No. Hei 5-146279 or JapanesePatent Application Laid-Open No. Hei 7-177896.

Although the aqueous solution containing oxidized glutathione may be anyaqueous solution containing oxidized glutathione, an aqueous solutionhaving a purity of oxidized glutathione in dissolved components of 50%or higher is preferred and an aqueous solution having a purity of 70% orhigher is more preferred. The aqueous solution may contain other organicsolvents, including alcohols such as methanol, ethanol, isopropylalcohol, n-propanol and the like, and ketones such as acetone, methylethyl ketone and the like. The aqueous solution preferably has a watercontent of 20% or higher. Particularly, examples thereof may include anaqueous solution prepared, for example, by pretreatment of a solution ofoxidized glutathione (this solution of oxidized glutathione has the samemeaning as the above-defined solution of oxidized glutathione).

The pretreatment method may include membrane treatment, gel filtrationtreatment, active carbon treatment, ion exchange resin treatment,synthetic adsorbent resin treatment, chelate resin treatment, solventprecipitation and the like, preferably active carbon treatment, ionexchange resin treatment, synthetic adsorbent resin treatment, solventprecipitation and the like, and among them, synthetic adsorbent resintreatment or ion exchange resin treatment is more preferred, and suchtreatments may be used in combination as appropriate.

In addition, the aqueous solution containing oxidized glutathione ispreferably an aqueous solution having a concentration of oxidizedglutathione contained therein of 50 to 700 g/L. Particularly, an aqueoussolution having a concentration of 100 to 400 g/L is preferred, and suchsolutions are prepared suitably, for example, by concentration and thelike.

As a water miscible organic solvent, any organic solvents miscible withwater may be used, but preferred examples thereof include alcohols, suchas methanol, ethanol, isopropyl alcohol, n-propanol and the like, andketones, such as acetone, methyl ethyl ketone and the like.

As a synthetic adsorbent resin, for example, a nonpolar porous adsorbentresin or the like may be used, and particular examples thereof mayinclude Diaion HP series (for example, HP10, HP20, HP21, HP30, HP40,HP50 and the like, manufactured by Mitsubishi Chemical Corporation),Diaion SP800 series (for example, SP800, SP825, SP850, SP875 and thelike, manufactured by Mitsubishi Chemical Corporation), Diaion SP200series (for example, SP205, SP206, SP207, SP207SS and the like,manufactured by Mitsubishi Chemical Corporation), AMBERLITE XAD series(for example, XAD4, XAD7HP, XAD 16, XAD 1600 and the like, manufacturedby Rhom and Hass Company), and the like. Among them, SP207 is preferred.

An ion exchange resin may include a strongly basic anion exchange resin,a weakly basic anion exchange resin, a strongly acidic cation exchangeresin, a weakly acidic cation exchange resin and the like.

Examples of a strongly basic anion exchange resin may include Diaion PAseries (for example, PA306, PA312, PA412 and the like, manufactured byMitsubishi Chemical Corporation) and the like, and examples of a weaklybasic anion exchange resin may include Diaion WA series (for example,WA10, WA20, WA30 and the like, manufactured by Mitsubishi ChemicalCorporation) and the like.

Examples of a strongly acidic cation exchange resin may includeAMBERLITE IR series (for example, 124 Na, 252 Na and the like,manufactured by Organo Corporation), Dowex (for example, XUS-40232.01and the like, manufactured by Dow Chemical Company) and the like, andexamples of a weakly acidic cation exchange resin may include AMBERLITEIRC series (for example, IRC-50, IRC-70 and the like, manufactured byRhom and Hass Company) and the like.

The non-crystalline amorphism of oxidized glutathione may be anon-crystalline amorphism obtained by drying oxidized glutathionehexahydrate, and the non-crystalline amorphism may be determined by lackof specific peaks at specific diffraction angles in the analysis basedon powder X-ray diffractometry. Therefore, even if oxidized glutathionecontains a little bit of crystals as observed by an electron microscopeand the like, it is included in the non-crystalline amorphism of thepresent application as long as it can be decided as being amorphous inthe analysis based on powder X-ray diffractometry.

Next, an example of a process for producing a non-crystalline amorphismof oxidized glutathione will be described in detail.

1. Preparation of Aqueous Solution Containing Oxidized Glutathione

According to the method described in Japanese Patent ApplicationLaid-Open No. Hei5-146279, or Japanese Patent Application Laid-Open No.Hei7-177896, reduced glutathione is oxidized, for example, with oxygen,hydrogen peroxide, enzyme capable of oxidizing ascorbic acid or the liketo obtain an aqueous solution, culture solution, yeast extract solution,bacteriostatic solution or the like, containing oxidized glutathione.This may be subjected optionally to pretreatment such that a purity ofoxidized glutathione in dissolved components may be 50% or higher,preferably 70% or higher.

The pretreated solution or untreated solution is concentrated to aconcentration of oxidized glutathione contained therein of 50 to 700g/L, preferably 100 to 400 g/L, thereby obtaining an aqueous solutioncontaining oxidized glutathione. In addition, the aqueous solutioncontaining oxidized glutathione may also be obtained by freeze-dryingthe pretreated solution or untreated solution to obtain powder, anddissolving the powder in water to the same concentration as mentionedabove. Herein, oxidized glutathione commercially available as powder mayalso be used.

A pretreatment method for obtaining an aqueous solution containingoxidized glutathione may include membrane treatment, gel filtrationtreatment, active carbon treatment, ion exchange resin treatment,synthetic adsorbent resin treatment, chelate resin treatment (examplesof a chelate resin used for chelate resin treatment include Duolite C467 manufactured by Sumitomo Chemical Co., Ltd., and the like), solventprecipitation and the like, preferably active carbon treatment, ionexchange resin treatment, synthetic adsorbent resin treatment, solventprecipitation and the like, and among them, synthetic adsorbent resintreatment or ion exchange resin treatment is more preferred, and suchtreatments may be used in combination as appropriate.

More particularly, for example, an aqueous solution, culture solution,yeast extract solution, bacteriostatic solution or the like, containingoxidized glutathione, may be loaded to a synthetic adsorbent resin,preferably SP207, and subjected to separation and purification using, asan eluent, water or a water miscible organic solvent (the water miscibleorganic solvent has the same meaning as defined above) alone or incombination of two or more, or an aqueous solution, culture solution,yeast extract solution, bacteriostatic solution or the like, containingoxidized glutathione, may be loaded to a strongly acidic cation exchangeresin (H⁺ type) having a crosslinking degree of 12% or more, preferablySK112 or SK116, and then loaded to a strongly acidic cation exchangeresin (H⁺ type) having a crosslinking degree of 4% or less, preferablySK102 or XUS-40232.01, and subjected to separation and purification byelution with an eluent which is mixed with water or a water miscibleorganic solvent (the water miscible organic solvent has the same meaningas defined above) alone or in combination of two or more, aqueousammonia solution, aqueous sodium chloride solution or the like, therebyobtaining an aqueous solution containing oxidized glutathione havinghigh purity.

As the starting reduced glutathione, a commercially available product oran aqueous solution, purified solution or freeze-dried powder containingreduced glutathione obtained by a synthetic method, fermentation methodor yeast extraction method according to a known method (for example, amethod described in Japanese Patent Publication No. Sho44-239, JapanesePatent Publication No. Sho46-4755, Japanese Patent Publication No.Sho46-2838 or Japanese Patent Application Laid-Open No. Sho61-74595 orthe like) may be used.

2. Production of Crystal of Oxidized Glutathione Hexahydrate

The aqueous solution containing oxidized glutathione obtained from 1. isadjusted to a pH of 2.5 to 3.5 with hydrochloric acid or sulfuric acidor aqueous solution of sodium hydroxide or the like as necessary, andthen the aqueous solution is allowed to stand or is stirred at atemperature of −20 to 15° C., preferably 0 to 10° C., for 1 minute to 48hours, more preferably 1 to 24 hours to perform cooling crystallization.In addition, crystallization may be carried out by cooling to thecorresponding temperature over 1 minute to 48 hours, preferably 1 to 24hours.

In addition, when carrying out cooling crystallization, a solventselected from alcohols and ketones may be added or added dropwise to theaqueous solution containing oxidized glutathione, thereby precipitatinga crystal of oxidized glutathione hexahydrate.

Examples of alcohol solvents include ethanol, propanol, n-propanol,isopropyl alcohol and the like, and examples of ketone solvents includeacetone, methyl ethyl ketone and the like.

The solvent may be added in an amount of 0.1 to 100 times, preferably0.1 to 10 times, and more preferably 0.1 to 3 times of the aqueoussolution containing oxidized glutathione. In addition, when addingdropwise the solvent, the above-defined amount of solvent may be addeddropwise over 1 minute to 10 hours, preferably 1 to 7 hours.

When carrying out cooling crystallization, whether or not the solvent isadded or added dropwise, a seed crystal may be added as necessary. Theseed crystal may be added at a concentration of 0.001 to 50 g/L,preferably 0.01 to 5 g/L, and when added dropwise, they may be addeddropwise until the final concentration becomes the above-definedconcentration.

The precipitated crystal is separated, for example, by centrifugalfiltration, decantation or the like, washed with water or a watermiscible organic solvent, and then the obtained crystal is dried underreduced pressure or ventilation, thereby obtaining a crystal of oxidizedglutathione hexahydrate. In addition, the crystal may be furtherpurified by further operation such as washing, drying, recrystallizationand the like.

The crystal of oxidized glutathione hexahydrate obtained by theabove-described method may be obtained as an adduct with various watermiscible organic solvents, but such an adduct with various watermiscible organic solvents is also included in the crystal of the presentapplication.

In addition, there is a case where crystals having a different crystaltype or a different particle size may be present in the crystal ofoxidized glutathione hexahydrate obtained by the above method, and theymay be obtained alone or in a mixture, but such crystals having adifferent crystal type or particle size alone or in a mixture are alsoincluded in the crystal of the present application.

3. Production of Non-Crystalline Amorphism of Oxidized Glutathione

The crystals of oxidized glutathione hexahydrate obtained from 2. may bedried by a dryer at a temperature of 40 to 90° C., preferably 50 to 80°C., and more preferably 60 to 70° C. to obtain a non-crystallineamorphism of oxidized glutathione. The drying time may be determinedsuitably depending on drying temperature and amount of the crystal ofoxidized glutathione hexahydrate, and it is preferred that drying iscarried out while checking transition from the crystal to anon-crystalline amorphism.

The dryer may be any type as long as it can dry efficiently the amountof the crystal of oxidized glutathione provided for drying, butparticular examples of the dryer may include a conical dryer, box typeshelf dryer, box type hot air dryer, fluidized bed dryer, band typedryer and the like, and a conical dryer is preferred. In addition, it ispossible to increase drying efficiency by placing the inside of a dryerunder reduced pressure during drying.

For example, 15 g of the crystal of oxidized glutathione hexahydrate maybe charged to a conical dryer and dried at 60° C. under reduced pressure(40 mmHg) for 12 hours to obtain a non-crystalline amorphism oxidizedglutathione.

EXAMPLE 1

Production of Crystal of Oxidized Glutathione Hexahydrate (1)

The freeze-dried powder (3.0 g) of oxidized glutathione obtained fromReference Example 1 was dissolved in water to provide an aqueoussolution containing oxidized glutathione (30 mL, concentration ofoxidized glutathione: 100 g/L). The aqueous solution was allowed tostand at 5° C. for 48 hours to precipitate a crystal. The precipitatedcrystal was separated by filtration and dried under ventilation toobtain the crystal (1.0 g) of oxidized glutathione hexahydrate. Inaddition, single crystal X-ray structural analysis showed that thecrystal is provided as hexahydrate.

Hereinafter, physicochemical properties of the obtained oxidizedglutathione hexahydrate will be described.

Hydration number: hexahydrate

Melting point: 191° C.

Powder X-Ray Diffraction [diffraction angle (2θ°), the number in aparenthesis indicates a relative intensity ratio (I/I₀)]: 8.12° (100),9.70° (33), 10.62° (43), 12.44° (14), 14.20° (13), 16.22° (71), 16.38°(22), 17.90° (18), 18.90° (9), 19.52° (76), 20.26° (17), 21.32° (13),21.60° (22), 22.82° (41), 23.34° (26), 24.40° (34), 24.72° (23), 24.98°(33), 25.56° (12), 26.18° (18), 26.68° (34), 27.20° (9), 28.32° (12),29.00° (13), 29.66° (11), 31.02° (10), 31.58° (10), 32.20° (9), 32.72°(11), 32.88° (12), 34.48° (18) and 41.56° (13).

The following Table 1 shows the results of comparison between thesaturation solubility of the crystal of oxidized glutathione hexahydrateobtained as described above and that of oxidized glutathionemonohydrate.

TABLE 1 Saturation solubility of the crystal of oxidized glutathionehexahydrate Saturation solubility (g/L) <H₂O, 30° C.> oxidizedglutathione hexahydrate 173 oxidized glutathione monohydrate 13.5

EXAMPLE 2

Production of Crystals of Oxidized Glutathione Hexahydrate (2)

The freeze-dried powder (10.0 g) of oxidized glutathione obtained fromReference Example 1 was dissolved in water to provide an aqueoussolution containing oxidized glutathione (33 mL, concentration ofoxidized glutathione: 300 g/L). The aqueous solution was cooled to 5°C., and the crystal (0.1 g) obtained from Examples 1 was added theretoas a seed crystal. To the resultant solution, methanol (66 mL) was addedover 5 hours to perform crystallization. The crystallization solutionwas aged for 1 hour, and the precipitated crystal was separated byfiltration, and dried under ventilation to obtain the crystal (8.5 g) ofoxidized glutathione hexahydrate.

EXAMPLE 3

Production of Crystal of Oxidized Glutathione (3)

An aqueous solution containing reduced glutathione obtained according tothe method described in Example 2 of Japanese Patent ApplicationLaid-Open No. Sho61-74595 was adjusted to pH 7.5 with an aqueous sodiumhydroxide solution according to the method described in Japanese PatentApplication Laid-Open No. Hei 5-146279, and then oxygen was blown intothe system to perform oxidation, thereby obtaining an aqueous solutioncontaining oxidized glutathione (48.1 L, concentration of oxidizedglutathione: 18.0 g/L).

This aqueous solution was adjusted to pH 3.0 with sulfuric acid, andsubjected to bacteriostatic treatment to obtain a bacteriostaticsolution of oxidized glutathione (55.5 L, concentration of oxidizedglutathione: 14.4 g/L). The bacteriostatic solution was loaded to DiaionSK116 (22 L) and then, loaded to Dowex XUS-40232.01 (13 L) to performadsorption of oxidized glutathione, thereby eluting the oxidizedglutathione with an aqueous ammonia solution (20 L, concentration: 2mol/L).

This eluate was loaded to SK116 (7 L) to make a free form and to removeammonia, thereby obtaining an aqueous solution containing oxidizedglutathione (19 L, concentration of oxidized glutathione: 35.4 g/L). Tothe aqueous solution, active carbon (130 g) was added, followed bystirring at 40° C. for 1 hour, and then active carbon was removed byfiltration. The obtained filtrate was concentrated to 2.24 L(concentration of oxidized glutathione: 300 g/L), and cooled to 5° C.

To the concentrate, the crystal (13 g) obtained by the method describedin Example 1 was added as a seed crystal, and methanol (4.6 L) was addedover 5 hours to perform crystallization. The precipitated crystal wasseparated by filtration, and dried under ventilation to obtain thecrystal (610 g) of oxidized glutathione hexahydrate.

EXAMPLE 4

Production of Non-Crystalline Amorphism of Oxidized Glutahione

The crystals (15.0 g) of oxidized glutathione hexahydrate obtained fromExample 3 were charged to a conical dryer, and dried at 60° C. underreduced pressure (40 mmHg) for 12 hours to obtain a non-crystallineamorphism (12.7 g) of oxidized glutathione.

REFERENCE EXAMPLE 1

Acquisition of Freeze-Dried Powder of Oxidized Glutathione

After 4.8 g of reduced glutathione obtained by the method described inJapanese Patent Application Laid-Open No. Hei 5-146279 was dissolved inwater (24 mL), the obtained aqueous solution containing reducedglutathione was adjusted to pH 7.5 with an aqueous sodium hydroxidesolution, and stirred in the presence of copper sulfate. The reactionmixture was loaded to Diaion SK116 (32 mL) and Duolite C467 (4 ml,Sumitomo Chemical Co. Ltd.), and the treated solution was concentratedto obtain an aqueous solution containing oxidized glutathione (11 mL,concentration of oxidized glutathione 300 g/L). The aqueous solution wasfreeze-dried to obtain 3.0 g of freeze-dried powder of oxidizedglutathione.

Industrial Applicability

According to the present invention, there are provided a non-crystallineamorphism of oxidized glutathione useful as a product, raw material,intermediate or the like of health-aid food, pharmaceuticals, cosmeticsand the like, and a process for producing thereof.

The invention claimed is:
 1. A process for producing a non-crystallineamorphism of oxidized glutathione comprising (a) treating a solutioncontaining oxidized glutathione with a synthetic adsorbent resin or ionexchange resin to provide an aqueous solution containing oxidizedglutathione, (b) cooling the aqueous solution containing oxidizedglutathione to 15° C. or lower and adding or adding dropwise methanol tothe aqueous solution to precipitate a crystal of oxidized glutathionehexahydrate, (c) collecting the crystal of oxidized glutathionehexahydrate from the aqueous solution, and (d) drying the crystal ofoxidized glutathione hexahydrate at a temperature of 40 to 90° C. toproduce a non-crystalline amorphism of oxidized glutathione.
 2. Theprocess for producing a non-crystalline amorphism of oxidizedglutathione according to claim 1, wherein the crystal of oxidizedglutathione hexahydrate is the crystal of oxidized glutathionehexahydrate having peaks at a diffraction angle (2θ) of 8.12°, 9.70°,10.62°, 12.44°, 14.20°, 16.22°, 16.38°, 17.90°, 18.90°, 19.52°, 20.26°,21.32°, 21.60°, 22.82°, 23.34°, 24.40°, 24.72°, 24.98°, 25.56°, 26.18°,26.68°, 27.20°, 28.32°, 29.00°, 29.66°, 31.02°, 31.58°, 32.20°, 32.72°,32.88°, 34.48° and 41.56° in powder X-ray diffraction.